Alcohol abuse and human immunodeficiency virus (HIV) infection are major public health problems in the United States and frequently coexist in the same individual. While several studies have shown a significant association between alcohol consumption and the risk of being infected with HIV, it remains to be determined whether this association is due to behavioral and/or biomedical mechanisms. Furthermore, existing data neither confirm nor disprove the hypothesis that alcohol can function as a cofactor to accelerate progression of HIV infection. Studies of HIV-infected patients are inherently limited in their ability to control for variables such as timing and dose of HIV exposure, nutrition, concurrent use of other drugs of abuse, use of highly active anti-retroviral therapy, as well as the frequency and amount of alcohol consumed. This lack of knowledge on the effect of alcohol on HIV infectivity and disease progression is a major impediment in understanding HIV-related morbidity and mortality. In order to study the impact of alcohol consumption on HIV infection, we have developed a model of chronic alcohol consumption in rhesus macaques infected with simian immunodeficiency virus (SIV). Our studies show that alcohol increases the viral set point in SIV-infected alcohol-consuming macaques, which is predictive of survival, and enhances the effect of an opportunistic infection on viral replication. We now plan to identify the immunologic mechanisms involved and propose the following Specific Aims: 1) to test the hypothesis that alcohol increases the plasma viral set point in SIV infected macaques by compromising viral specific T lymphocyte responses; 2) to test the hypothesis that SIV replication is upregulated in alveolar macrophages (AM) during experimental pneumococcal pneumonia and this upregulation is enhanced by alcohol consumption; 3) to test the hypothesis that the increase in SIV replication induced by an opportunistic pulmonary infection and enhanced by alcohol is mechanistically associated with activation of NF-kB in AM; and 4) to test the hypothesis that the proliferation of SIV induced by an opportunistic infection and enhanced by alcohol results in the selective replication of macrophage-tropic SIV genotypes and contributes to the evolution of novel phenotypic and antigenic variants. Addressing these specific aims in the context of a well-defined model of HIV infection will provide novel and important information on the pathogenesis of HIV infection in the alcohol-consuming host.